Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial

Abstract

Background: Protection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium-glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity.

Methods: This prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency-to-high-frequency (LF/HF) ratio from baseline to 24 weeks. Secondary endpoints were changes in other sudden cardiac death (SCD) surrogate markers such as HRT.

Results: Overall, 96 patients were included (46, empagliflozin group; 50, placebo group). The changes in SDANN were + 11.6 and + 9.1 ms in the empagliflozin (P = 0.02) and placebo groups (P = 0.06), respectively. Change in LF/HF ratio was - 0.57 and - 0.17 in the empagliflozin (P = 0.01) and placebo groups (P = 0.43), respectively. Significant improvement was noted in HRT only in the empagliflozin group (P = 0.01). Whereas intergroup comparison on HRV and HRT showed no significant difference between the empagliflozin and placebo groups. Compared with the placebo group, the empagliflozin group showed significant decreases in body weight, systolic blood pressure, and uric acid. In the empagliflozin group, no adverse events were observed.

Conclusions: This is the first randomized clinical data to evaluate the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and AMI. Early SGLT2 inhibitor administration in AMI patients with T2DM might be effective in improving cardiac nerve activity without any adverse events.

Trial registration: The EMBODY trial was registered by the UMIN in November 2017 (ID: 000030158). UMIN000030158; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034442 .

Keywords: Acute Myocardial Infarction; Heart rate turbulence; Heart rate variability; Randomized Controlled Trial; Sodium–glucose cotransporter 2 inhibitor; Sudden cardiac death.

Fig. 1

A total of 105 patients met the inclusion criteria and were randomized. Six patients in the empagliflozin group and three patients in the placebo group were excluded because of consent withdrawal before medication begun. Therefore, 96 patients were included in the full analysis set (46 in the empagliflozin group and 50 in the placebo group)

Fig. 2

Changes from baseline in the heart rate turbulence. The category of heart rate turbulence reflecting abnormal autonomic nerve activity improved significantly in the empagliflozin group only. Intergroup comparison revealed no significant difference

Fig. 3

Changes from baseline in the late potentials. Intragroup and intergroup comparison revealed no significant change in late potentials as an indicator of depolarization

Fig. 4

Changes from baseline in systolic blood pressure, body weight, and body mass index. The shifts in systolic blood pressure, body weight, and body mass index during the trial period are presented. Compared with the placebo group, the empagliflozin group showed an early improvement with a significant difference (Intergroup; P = 0.0005, P = 0.0002 and P = 0.0002, respectively)